Why are both Pfizer and Sanofi/Regeneron committing to such expensive clinical trials? After all, lowering LDL cholesterol via statin treatment is a proven method for treating heart disease. PCSK-9 is just another mechanism to do this. However, the FDA may require such data on a new mechanistic class of drugs BEFORE approval. After all, the statins are awfully safe and effective drugs. In addition, some believe that statins have other beneficial effects beyond LDL lowering that contribute to their effectiveness. Shouldn’t the drug sponsor demonstrate that a new drug is at least as good as existing therapy? Furthermore, there might also be another issue involved here. The PCSK-9 antibodies will be used on top of statin therapy. Most cardiologists will want to drive the LDL levels of their at-risk patients as low as possible. After all, the pharmaceutical industry has run many studies showing that “lower is better" when it comes to LDL cholesterol. However, can you go too low? Would there be health issues with patients whose LDL cholesterol dropped to less than 40mg/dL? My guess is that the FDA would like to know the answer to this before allowing these drugs on the market and one of Pfizer's studies will address this.

Beyond the FDA, however, is the issue of payers. This is where the real hurdle exists for acceptance of PCSK-9 inhibitors. As I said before, statins are safe and effective. It’s true that there are some patients for whom statins are poorly tolerated or not effective, but this is a relatively small niche. The developers of these drugs are going to want premium pricing for these antibodies which, by their nature, are far more expensive to produce than small molecules like statins. Also, these companies would want these drugs to be used in as broad a patient population as possible. But statins like Lipitor (generic: atorvastatin) are now inexpensive as their patents have expired and they are available generically. Payers are going to be extremely reluctant to reimburse payment for PCSK-9 antibodies unless they are vastly superior to statins. Is there a meaningful clinical benefit for a patient with heart disease to have an LDL cholesterol of 50mg/dL as opposed to an LDL cholesterol of 70mg/dL that is achievable with generic statins? Pfizer, Sanofi/Regeneron and, presumably, Amgen, will be investing a lot of money to try to prove that.

Some question the wisdom of these large investments. However, they are required to demonstrate the value of new medicines. Many industry critics bemoan that the biopharmaceutical industry historically would rarely do head-to-head comparisons of a new drug versus standard of care. Furthermore, many clinical trials for new drugs would test the drug in patients for 6 months or, at most, a year. As can be seen with the PCSK-9 antibodies, it is hard to be successful in the old paradigm. It is wise to operate in a manner that demonstrates the value of a new drug. But, there is no guarantee that your billion dollar total phase 3 program will succeed. As far as big bets go, the PCSK-9 bet looks like a good one. But we’ve been surprised before.